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FRIDAY, 15 JUNE 2018
FRI0335 Hematopoietic stem cell transplantation for autoimmune diseases – a 20 years single centre experience
T. Alexander1, L. Templin1, A. Grützkau2, H. Hirseland2, A. Thiel3, G. Burmester1, A. Radbruch2, R. Arnold4, F. Hiepe1
Abstract
Background Over the past 20 years, hematopoietic stem cell transplantation (HSCT) has been emerging as a promising treatment option for severe cases of autoimmune diseases (ADs). Meanwhile, positive results have been obtained in 3 randomised clinical trials for systemic sclerosis. The goal of this therapy is to induce medication-free remissions by ablating the pathologic autoreactive memory and restoring of self-tolerance.
Objectives Here, we summarise the clinical outcomes of AD patients receiving HSCT at the Charité – University Medicine.
Methods In this prospective study, the outcome of 22 patients been analysed after receiving a CD34+-selected autologous HSCT after immunoablation with ATG and cyclophosphamide for different ADs (10 SLE, 4 SSc, 3 vasculitis, 2 multiple sclerosis, 1 polychondritis, 1 inflammatory polyneuropathy, 1 autoimmune haemolytic anaemia) between 1998 and 2015. Multiparamteric flow cytometry was applied to characterise peripheral blood lymphocytes subsets including analysis of the TCR-Vbeta repertoire on CD4+ T cells, CD31 expression as marker for thymic output of CD4+ T cells, including Foxp3+ Tregs. In SLE, Siglec-1 on monocytes as surrogate for interferon activity and RNA expression profiling by microarray of FACS-sorted CD14+ monocytes was performed (Affymetrix). Autoantibodies were investigated with ELISA.
Results With a median follow-up of 135 months, the overall survival was 76.5% and progression-free survival 67.9%, respectively. 3 deaths were regarded treatment related, 1 patient had persisting disease (haemolytic anaemia) and 4 relapses occurred in SLE at 1, 18, 36 and 80 months, respectively. Remaining patients are in stable clinical remissions despite discontinuation of immunosuppressive therapy. HSCT was associated with significant reduction or normalisation of autoantibody levels and a profound reconfiguration of the adaptive immune system, the latter characterised by a re-emergence of naďve T cells with markers of recent thymic emigrants and renewed TCR repertoire, including Foxp3+ Tregs and regeneration of naďve B cells. In SLE patients, Siglec-1 expression on monocytes completely normalised and transcriptome analysis revealed an abrogation of type I interferon signalling in responding patients.
Conclusions Our data provide the …proof-of-concept“ that a chronic autoimmune system can be reset into a naďve and self-tolerant state by HSCT, potentially providing cure in AD. Although applied as salvage therapy in severely affected patients with poor outcomes, TRM gradually improved due to accumulating centre experience and better patient selection and supportive care. Based on positive results from RCT in the major indications, HSCT should be placed earlier in the treatment algorithm, especially in systemic sclerosis with rapid progress and lung involvement.
FRI0335 Hematopoietic stem cell transplantation for autoimmune diseases – a 20 years single centre experience
T. Alexander1, L. Templin1, A. Grützkau2, H. Hirseland2, A. Thiel3, G. Burmester1, A. Radbruch2, R. Arnold4, F. Hiepe1
Abstract
Background Over the past 20 years, hematopoietic stem cell transplantation (HSCT) has been emerging as a promising treatment option for severe cases of autoimmune diseases (ADs). Meanwhile, positive results have been obtained in 3 randomised clinical trials for systemic sclerosis. The goal of this therapy is to induce medication-free remissions by ablating the pathologic autoreactive memory and restoring of self-tolerance.
Objectives Here, we summarise the clinical outcomes of AD patients receiving HSCT at the Charité – University Medicine.
Methods In this prospective study, the outcome of 22 patients been analysed after receiving a CD34+-selected autologous HSCT after immunoablation with ATG and cyclophosphamide for different ADs (10 SLE, 4 SSc, 3 vasculitis, 2 multiple sclerosis, 1 polychondritis, 1 inflammatory polyneuropathy, 1 autoimmune haemolytic anaemia) between 1998 and 2015. Multiparamteric flow cytometry was applied to characterise peripheral blood lymphocytes subsets including analysis of the TCR-Vbeta repertoire on CD4+ T cells, CD31 expression as marker for thymic output of CD4+ T cells, including Foxp3+ Tregs. In SLE, Siglec-1 on monocytes as surrogate for interferon activity and RNA expression profiling by microarray of FACS-sorted CD14+ monocytes was performed (Affymetrix). Autoantibodies were investigated with ELISA.
Results With a median follow-up of 135 months, the overall survival was 76.5% and progression-free survival 67.9%, respectively. 3 deaths were regarded treatment related, 1 patient had persisting disease (haemolytic anaemia) and 4 relapses occurred in SLE at 1, 18, 36 and 80 months, respectively. Remaining patients are in stable clinical remissions despite discontinuation of immunosuppressive therapy. HSCT was associated with significant reduction or normalisation of autoantibody levels and a profound reconfiguration of the adaptive immune system, the latter characterised by a re-emergence of naďve T cells with markers of recent thymic emigrants and renewed TCR repertoire, including Foxp3+ Tregs and regeneration of naďve B cells. In SLE patients, Siglec-1 expression on monocytes completely normalised and transcriptome analysis revealed an abrogation of type I interferon signalling in responding patients.
Conclusions Our data provide the …proof-of-concept“ that a chronic autoimmune system can be reset into a naďve and self-tolerant state by HSCT, potentially providing cure in AD. Although applied as salvage therapy in severely affected patients with poor outcomes, TRM gradually improved due to accumulating centre experience and better patient selection and supportive care. Based on positive results from RCT in the major indications, HSCT should be placed earlier in the treatment algorithm, especially in systemic sclerosis with rapid progress and lung involvement.
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